Phenanthridine derivatives, methods of producing them and medicaments containing phenanthridine derivatives

ABSTRACT

The invention relates to phenanthridine derivatives of the general formula I and II ##STR1## and also its salts, in which R 1  means a hydrogen atom, an aromatic, carbocyclic or hetercyclic or heterocyclic residue and in which R 2  and R 3 , which can be the same or different, mean a hydrogen atom, an alkyloxy residue, an alkylenoxy residue, a halogen atom or a nitro group.

This application is a 371 of PCT/DE 96/01958, now WO 97/14683 publishedApr. 24, 1997.

BACKGROUND OF THE INVENTION

The invention relates to new phenanthridine derivatives, which have anamino-group in position 6, a method for their production and forproducing medicines containing phenanthridine derivatives.

Presently known syntheses of benzo(c)phenanthridine, its 11,12dihydro-derivatives and similar compounds are very complex. The methodsof Robinson et al. concerning the Bischler-Napieralski cyclisation andalso of Ninomiya et al. using photocyclisation by Enamiden or by Shammaet al. and Cushman et al. concerning the Dickman-Thorpe-cyclisationshould be mentioned here, said methods all extending over a great numberof reaction steps (see I. Ninomya and T. Naito: Synthesis of thebenzo(c)phenanthridine alkaloids. Recent. Dev. Nat. Carbon compd. 10,11-90 (1984) and the literature mentioned there). p Furthermore,benzo(c)phenanthridine derivatives and their anti-tumour effect areknown from Pharmacy 44 pp. 593-597 (1989). Further phenanthridinederivatives are described in Tetrahedron 49 pp. 10305-10316 (1993) andin J. Chem. Soc. Perkin Trans. I, pp. 1137-1140 (1983) and in J. Me.Chem. 36, pp. 3686-3692 (1993). In the publications in J. Med. Chem. andTetrahedron, derivatives with an amino-group in position 6 were alsoindeed described, said amino-group being substituted however in everycase. Other derivatives have up till now not become known. This can beattributed mainly to the fact that the presently known derivatives arebased on synthesis methods which are costly and complex. Thereforeproduction of other phenanthridine derivatives was up till now notpossible.

OBJECT OF THE INVENTION

This assumed, it is the object of the present invention to make knownnew phenanthridine derivatives, a method for their production and theirapplication.

The object is achieved, with respect to the phenanthridine derivatives,by the characterising features of claim 1 and, with respect to theproduction method, by the features of claim 5. The application accordingto the invention of these phenanthridine derivatives is mentioned inclaim 10. The subclaims demonstrate advantageous further developments.

According to claim 1, the new phenanthridine derivatives are defined bythe general formulae I and II, ##STR2## in which R₁ means a hydrogenatom, an aromatic or heterocyclic residue, and R₂ and R₃, which can bethe same or different, mean hydrogen atoms an alkyl-oxy residue, analkylene-oxy residue, a halogen atom or a nitro group.

By an aromatic carbocyclic residue R₁ can be understood particularlysuch residues as are derived from benzene, naphthalene, anthracine,phenanthrene and pyrene. By an aromatic heterocyclic residue R₁ can beunderstood particularly residues, which are derived from furane,thiophene, pyridine, 1,2,4-oxdiazole, 1,2,3-triazole, benzofurane,benzoxazole, benzimidazole, benzthiazole, also the correspondingnaphtho-analogues of the type named benzo-five ring heterocyclenes andfrom indole, quinolene and isoquinolene. The aromatic carbocyclic orheterocyclic residues can be substituted once or several times.

For this purpose, as substitutes under the reaction conditions, inertgroups and/or atoms may be considered such as mono-amino groups, alkylamino groups, dialkyl amino groups, alkyl groups, alkoxyl groups,alkylene oxy groups and halogens.

On the basis of the found pharmacological characteristics, thederivatives which are of particular importance are those in which R₂ andR₃ hydrogen, and R₁ hydrogen are an unsubstituted phenyl residue, aphenyl residue with one or several methoxyl groups or a N,N-dimethylamino function. For this purpose, those derivatives in which R₁ is asubstituted or unsubstituted phenyl residue, in particular2,4-dimethoxyphenyl or 3,4-dimethoxyphenyl, may be emphasized. The2,4-dimethoxyphenyl derivative is particularly preferred here. Thephenanthridine derivatives according to the invention readily formphysiologically acceptable salts. Such salts are e.g. salts withinorganic and organic acids, e.g. dihydrochloride, hydrobromide andsulphates. Particularly well suited salts of organic acids are formedwith aliphatic mono- and di-carbon acids. Examples of such salts areacetates, maleates and fumarates.

The compounds were able to be confirmed by IR- and HNMR-analysis.

The invention relates furthermore to a method for producingphenanthridine derivatives. The applicant was able to show surprisinglythat it is possible to obtain the phenanthridine derivatives accordingto the invention by smean replacing appropriately substituted aldehydeswith appropriately substituted methobenzonitrile. Carrying on in detailat this stage with transformation of an aldehyde of Formula III

    R.sub.1 --CHO                                              III

R₁ having the previously mentioned meaning and with 2 mol of a2-methylbenzonitrile of Formula IV ##STR3## and R₂ and R₃ having thepreviously mentioned meaning, are introduced in the presence of a baseand an aprotic dipolar solvent and after isolation in a further stepaccording to generally valid methods, dehydration results with anappropriate dehydration medium in the presence or absence of solvent.The reaction process can be represented as follows: ##STR4##

Preferably, amides such as dimethylformamide, dimethylacetamide,diethylacetamide, hexamethyl-phosphoric acidtrisamide and carbamidessuch as tetramethyl carbamide, 1,3-dimethyltetrahydro-2-pyrimidinon and1,3-dimethylimidazolidinon or dimethylsulphoxide may be used as aproticdipolar solvent for the reaction according to the invention.

Alkali hydrides or alkaline earth hydrides such as sodium hydride,alkali amides such as sodium amide, sodium methyl acetamide, alkalialcoholate, alkaline earth alcoholates or aluminum alcoholates such aspotassium-tert-butylate, sodium methylate, sodium ethylate or aluminiumethylate can for example be used as a base.

The reaction can be conducted as follows: on to a solution of a base inan appropriate dipolar aprotic solvent, a solution of the compounds IIIand IV in the same solvent is dropped slowly in an inert gas atmosphere.After agitating for several hours at 35° C. to 50° C. in an inert gasatmosphere the product is poured on to ice-cold water and shaken outwith an appropriate organic solvent. The organic phase is reduced and,separated from the residue by introducing a halogen hydrogen acid or byshaking with an appropriate inorganic or organic acid, the6-amino-11,12-dihydrobenzo(c)phenanthridine II is precipitated or isisolated, by using an aqueous acid solution, from the aqueous phaseafter neutralisation and removal of the base. The6-amino-11,12-dihydrobenzo(c)phenanthridine II can then be dehydrated tothe 6-aminobenzo(c)phenanthridine I, according to generally acceptedmethods, with an appropriate dehydration medium in the presence orabsence of an inert solvent.

It should be emphasized especially, in the method according to theinvention, that phenanthridine derivatives, which have a substituted oran unsubstituted phenyl residue in position-11, are hereby synthesized.It is surprising that the synthesis is possible by means of the simplereaction which is described here, in which a great variation in rangeexists on the basis of the original substances which are put in withrespect to the educts which can be obtained.

It was then found that the previously described phenanthridinederivatives possessed excellent anti-tumour, anti-microbial,anti-fungicidal, anti-viral and anti-inflammatory properties. In orderto examine the pharmacological properties, the compounds of the generalFormula I and II were examined in an "in-vitro-Antitumor-Screening" ofthe National Cancer Institute (NCI), Bethesdal, Md., USA. About 58different human pathogenic tumour cell series, which stemmed from ninetypes of cancer (leukaemia, non-small cell lung carcinoma, largeintestine cancer, central nervous system cancer, melanoma, ovariancancer, renal cancer, prostate cancer and breast cancer). In order todetermine the level of efficacity, tumour cells were subjected to thecompounds over two days and subsequently the inhibition of growth wasdetermined indirectly via the calculation of the protein biomass withsulphorhodomine B. Untreated cultures served as a reference.

In these experiments,6-amino-11-(2,4-dimethoxyphenyl)benzo(c)phenanthridiniumperchlorate forexample showed inhibitions of growth. Surprisingly, the compoundindicates activities which lie outwith the category of anti-tumourcompounds studied in a similar manner, with the result that a completelynew spectrum of effect is achieved.

BRIEF DESCRIPTION OF THE DRAWINGS

From the present data, dosage-effect curves are depicted in FIGS. 1 to 9for this compound for example. The nine different figures contain thevarious forms of cancer. The percentage growth respectively is plottedwith respect to the concentration of compound (as log₁₀ of the molarconcentrations). The individual curves of each type of cancer aredifferent cell strains of this form of cancer, which appear as keys intheir normal abbreviations. Horizontal lines in the Figures indicatepercentage growth of +100, +50, 0, -50 and -100. 100% growth indicatesfor example no change in growth after two days without supplement ofsubstance. It can be seen in the individual curves that with increasingconcentrations of the substance the percentage growth declines.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The invention also relates therefore to medicines containingphenanthridine derivatives which are described here. The medicinecontains, for this purpose, at least one phenanthridine derative, in themanner described here, together with at least one inert pharmaceuticallyacceptable carrier or dilution medium. A derivative of the generalFormula 1 is preferred as a phenanthridine derivative in which R₁ is a2,4-methoxyphenyl residue and R₂ and R₃ are hydrogen. The compound,according to the invention, can be administered orally, topically orparenterally, or in the form of suppositories. The preferred mode ofadministration is oral administration. This can be administered in theform of the base or as a physiologically acceptable salt. It isgenerally mixed with a pharmaceutically acceptable carrier or dilutionmedium, in order to create a medicine. For oral administration themedicine can be made available most usefully in the form of capsules ortablets or possibly even slow-release tablets. They can also beavailable in the form of dragees or in syrup form. Suitable topicpreparations are e.g. salts, lotions, creams, powders and sprays.

In the following, the invention is described in greater detail with thehelp of several embodiment examples.

EMBODIMENTS

Production of the 6-amino-11,12-dihydrobenzo(c)phenanthridine II:

EXAMPLE 1

6-amino-11,12-dihydrobenzo(c)phenanthridiniumchloride

A solution of 2.47 g (22 mmol) KOBu^(t) in 20 ml DMPU in a nitrogenatmosphere is prepared and a solution of 300 mg (10 mmol)paraformaldehyde and 2.34 g (20 mmol) 2-methylbenzonitrile in 12 ml DMPUis dropped slowly into the preparation in portions of 2 ml at a spacingof 15 minutes in a contra-flow of nitrogen. After six hours' agitationat 35° C. in a nitrogen atmosphere the product is poured on to asolution of 2.2 g (40 mmol) ammonium chloride in 100 ml ice water andshaken out three times with 100 ml dichloromethane. The combined organicphases are filtered through wadding, rotated to approx. 100 ml andshaken vigorously with 3 N hydrochloric acid. The detached organic phaseis further rotated until there is heavy precipitation, then being placedin the fridge overnight. The precipitation is stopped, washed with alittle dichloromethane, dried and recrystallised out ofmethanol/dichloromethane.6-amino-11,12-dihydroben-zo(c)phenanthridiniumchloride is obtained. Paleyellow platelets, yield: 16% of theoretical yield, melting point 350°C.--IR (KBr): ν=3244 cm⁻¹, 3102, 2946, 1654, 1630, 1616.--¹ H NMR (360MHz, [D₆ ]DMSO): δ=3.0 (mc, 2H, --CH₂ --), 3.08 (mc, 2 H, --CH₂ --),7.43 (mc, 3H, Ar--H), 7.77 (t, 1H, Ar--H), 8.02 (t, 1H, Ar--H), 8.16 (d,1H, Ar--H), 8.27 (mc, 1H, Ar--H), 8.60 (d, 1H, Ar--H), 9.49 (br, 2H,--NH₂), 13.78 (br, 1H, .tbd.N⁺ --H). C₁₇ H₁₅ N₂ Cl(292.77) Ber. C,72.21; H, 5.35; N, 9.91; Gef. C, 72.13; H, 5.35; N, 9.99.

EXAMPLE 2

6-amino-11,12-dihydro-11-phenylbenzo(c)iphenanthridiniumchloride

A solution of 1.06 g (10 mmol) benzaldehyde and 2.34 g (20 mmol)2-methylbenzonitrile in 5 ml DMPU is dropped slowly into a solution of2.47 mg (22 mmol) KOBu^(t) in 20 ml DMPU in a nitrogen gas atmosphere.After five hours' agitation at 35° C. in a nitrogen gas atmosphere theproduct is poured on to a solution of 2.2 g (40 mmol) ammonium chloridein 100 ml ice water, and shaken out three times with 100 mldichloromethane. The organic phase is filtered through wadding androtated roughly to 100 ml and shaken vigorously with 3 N hydrochloricacid. The resulting precipitation is suctioned off, washed withdichloromethane and dried. After recrystallisation frommethanol/dichloromethane6-amino-11,12-dihydro-11-phenylbenzo(c)-phenanthridiniumchloride isobtained. Bright yellow platelets, yield: 52% of theoretical yield,melting point 355° C.--IR (KBr): ν=3446 cm⁻¹, 3076, 1662, 1620, 1570.--¹H NMR (400 MHz, [D₆ ] DMSO): δ=3.18 (mc, 1H, 12-H), 3.56 (mc, 1H, 12-H),4.95 (mc, 1H, 11-H), 7.09 (mc, 5H, C6H5-), 7.24 (d, 1H, Ar--H), 7.35 (t,1H, Ar--H), 7.44 (t, 1H, Ar--H), 7.74 (mc, 1H, Ar--H), 7.91 (mc, 2H,Ar--H), 8.3 (d, 1H, Ar--H), 8.61 (d, 1H, Ar--H), 9.3 (br, 2H, --NH₂,),13.7 (br, 1H, .tbd.N⁺ --H).

C₂₃ H₁₉ N₂ Cl(358.87) Ber. C, 76.98; H 5.34; N, 7.81; Gef. C, 76.52; H,5.37N, 7.75.

EXAMPLE 3

6-amino-11,12-dihydro-11-(3,4-dimethoxyphenyl)benzo[c]phenanthridiniumchloride

Similar to Example 1. Light-yellow needles. Yield: 53% of theoreticalyield, melting point 205° C. (methanol/water). -IR (KBr): ν=3438 cm-,3268, 3106, 2938, 1648, 1616, 1584.--¹ H NMR (400 MHz, [D6] DMSO):δ=3.08 (mc, 1H, 12-H), 3.42 (mc, 1H, 12-H), 3.61 (s, 3H, --OCH₃), 3.99(s, 3H, --OCH₃), 5.02 (mc, 1H, 11-H), 6.04 (mc, 1H, Ar--H), 6.21 (mc,1H, Ar--H), 6.61 (mc, 1H, Ar--H), 7.20 (d, 1H, Ar--H), 7.34 (t, 1H,Ar--H), 7.43 (t, 1H, Ar--H), 7.63 (d, 1H, Ar--H), 7.73 (t, 1H, Ar--H),7.91 (t, 1H, Ar--H), 8.36 (d, 1H, Ar--H), 8.61 (d, 1H, Ar--H), 9.56 (br,2H, --NH₂), 13.85 (br, 1H, .tbd.N⁺ --H).

C₂₅ H₂₃ N₂ O₂ Cl (418. 92) Ber. C, 71.68; H, 5.53; N, 6.69; Gef. C,70.95; H, 5.37; N, 6.80.

Production of 6-aminobenzo(c)phenanthridine I:

EXAMPLE 1

6-aminobenzo(c)phenanthridiniumperchlorate

A solution of 404 mg (1.7 mmol) DDQ in 35 ml dioxan is added to asolution of 250 mg (1.02 mmol)6-amino-11,12-dihydrobenzo(c)phenanthridine in 15 ml dioxan and heatedfor four hours in a contra-flow situation. The cooled solution issubsequently poured on to a sodium hydrogen carbonate solution andshaken out with diethyl ether. The diethyl ether phase is washed oncewith diluted sodium hydrogen carbonate solution and three times withwater. After addition of 70% perchloric acid, precipitation is obtained.After drying out and recrystallising from methanol, brown needles,yield: 44% of theoretical yield, melting point 325° C. -IR (Kbr):ν=3404cm⁻¹, 3348, 3298, 3276, 3234, 1666, 1616.--¹ H NMR (300 MHz, [D₆ ]DMSO): δ=7.82 (mc,3H, Ar--H, 8.0 (d, 1H, Ar--H), 8.13 (mc, 2H, Ar--H),8.56 (mc, 2H, Ar--H), 8.69 (d, 1H, Ar--H), 8.83 (d, 1H, Ar--H), 9.73(br, 2H, --NH₂), 12.84 (br, 1H, .tbd.N⁺ --H).

C₁₇ H₁₃ N₂ O₄ Cl (344.06) Ber. C, 59.29; H, 3.81; N, 8.14; Gef. C,59.23; H, 3.83; N, 8.24.

EXAMPLE 2

6-amino-11-phenylbenzo[c]phenanthridiniumperchlorate

Similar to Example 1. Grey-brown needles, yield: 50% of theoreticalyield, melting point 345° C. -IR (KBr) ν=3412 cm⁻¹, 3358, 3310, 3226,1668, 1642, 1612.--¹ H NMR (300 MHz, [D6]DMSO): δ=7.51 (mc, 7H, Ar--H),7.80 (mc, 4H, Ar--H), 8.15 (d, 1H, Ar--H), 8.66 (mc, 2H, Ar--H), 9.88(br, 2H, --NH₂), 12.8 (br, 1H, .tbd.N⁺ --H).

C₂₃ H₁₇ N₂ O₄ Cl (420.09) Ber. C, 65.70; H, 4.08; N, 6.67; Gef. C,65.67; H, 4.03; N, 6.67.

EXAMPLE 3

6-amino-11-(2,4dimethoxyphenyl)benzo[c]phenanthridiniumperchlorate

Similar to Example 1. Dark brown needles, yield: 45% of theoreticallyyield, melting point 336° C. -IR (KBr): ν=3418 cm⁻¹, 3352, 3302, 3270,1660, 1608.--¹ H NMR (300 MHz, [D6] DMSO): δ=3.38 (s, 3H, --OCH₃), 3.87(s, 3H, --OCH₃), 6.69 (mc, 1H, Ar--H), 6.77 (mc, 1H, Ar--H), 7.34 (mc,1H, Ar--H), 7.77 (mc, 6H, Ar--H), 8.11 (mc, 1H, Ar--H), 8.77 (mc, 2H,Ar--H), 9.72 (br, 2H, --NH₂); 12.58 (br, 1H, .tbd.N⁺ --H).

C₂₅ H₂₁ N₂ O₆ Cl (480.19) Ber. C, 62.49; H, 4.41; N, 5.83; Gef. C,62.56; H, 4.30; N, 5.87.

We claim:
 1. A phenanthridine derivative of the Formula I and II##STR5## or their salts, wherein R₁ is selected from the groupconsisting of aromatic carbocyclic and heterocyclic residues, theheterocyclic residues are residues derived from the group consisting offurane, thiophene, pyridine, 1,2,4-oxdiazole, 1,2,3-triazole,benzofurane, benzoxazole, benzimidazole, benzthiazole, correspondingnaptho-analogues of the type named benzo-five ring heterocyclenes,indole, quinolene, and isoquinolene and R₂ and R₃ are the same ordifferent and are selected from the group consisting of hydrogen,alkyoxy residues, alkylene oxy residues, halogen atoms and nitro groups.2. The phenainthridine derivative according to claim 1, wherein R₂ andR₃ are hydrogen and R₁ is selected from the group consisting ofunsubstituted phenyl residues, phenyl residues with at least one methoxygroup, and phenyl residue with a N,N-dimethylamine.
 3. Thephenanthridine derivative according to claim 2, wherein R₁ is selectedfrom the group consisting of phenyl residues, 2,4-methoxyphenyl residuesand 3,4-methoxyphenyl residues.
 4. The phenanthridine derivativeaccording to claim 3, wherein R₁ is a 2,4-methoxyphenyl residue.
 5. Amethod for producing the phenanthridine derivative of the Formula IIaccording to claim 1, comprising: causing an aldehyde of the Formula III

    R.sub.1 --CHO

to react with a 2-methylbenzonitrile of the Formula IV ##STR6## in thepresence of bases in an aprotic, dipolar solvent, the residues R₁, R₂and R₃ possessing the meanings mentioned in claim 1 and with the provisothat R₁ can also be hydrogen.
 6. A method for producing thephenanthridine derivative of the general Formula I according to claim 1,comprising: causing an aldehyde of the Formula III

    R.sub.1 --CHO

to react with a 2-methylbenzonitrile of the Formula IV ##STR7## in thepresence of a base in an aprotic, dipolar solvent, the residues R₁, R₂and R₃ possessing the meanings mentioned in claim 1 and with theprovisio that R₁ can also be hydrogen and dehydrating a product of thereaction with a dehydration medium in the absence or presence ofsolvents.
 7. The method for producing phenanthridine derivativesaccording to claim 5, wherein an aldehyde of the Formula III is causedto react, R₁ being selected from the group consisting of phenylresidues, 2,4-methoxyphenyl residues, 3,4-methoxyphenyl residues andhydrogen.
 8. The method according to claim 6, wherein an aldehyde of theFormula III is caused to react, R₁ being selected from the group,consisting of phenyl residues, 2,4-methoxyphenyl residues,3,4-methoxyphenyl residues and hydrogen.
 9. The method according toclaim 7, wherein R₁ is selected from the group consisting of2,4-methoxyphenyl residues and 3,4-methoxyphenyl residues.
 10. Themethod according to claim 8, wherein R₁ is selected from the groupconsisting of 2,4-methoxyphenyl residues and 3,4-methoxyphenyl residues.11. The method according to claim 5, wherein a 2-methylbenzonitrile ofthe Formula IV is caused to react, R₂ and R₃ being hydrogen.
 12. Themethod according to claim 6, wherein a 2-methylbenzonitrile of thegeneral Formula IV is caused to react, R₂ and R₃ being hydrogen.
 13. Apharmaceutical composition comprising therapeutically effective amountof at least one of the phenanthridine derivatives of claim 1 togetherwith at least one inert, pharmaceutically acceptable carrier or dilutionmedium.
 14. The pharmaceutical composition according to claim 13,comprising therapeutically effective amount of a phenanthridinederivative of the Formula I, R₁ being a 2,4-methoxyphenyl residue and R₂and R₃ being hydrogen.